The proposed Tropical Medicine Research Center (TMRC) will build upon an established, productive and internationally recognized research program in malaria at the Faculty of Tropical Medicine, Mahidol University, and the National Science and Technology Developmental Agency (NSTDA) in Bangkok, Thailand, in a multi-disciplinary collaborative project designed to characterize the pathophysiology and therapy of malaria anemia in Thailand. Malaria provides the paradigm for a disease that has shaped the human genome through natural selection of protective genetic traits. More genes have now been implicated in variability of susceptibility to malaria than to any other infections or non- infectious disease of humans. Genes now recognized as affecting the host response to malaria include those for hemoglobin variants, for red blood cell enzymes, components of the membrane cytoskeleton, membrane receptors and blood group proteins, as well as loci that modulate immune responses or are involved in underlying pathophysiologic processes. To determine the roles of immunogenetic determinants of malaria anemia and of genetic factors altering response to anti-malarial therapy, a program of interrelated basic and clinical research projects has been developed. The specific aims of the three component projects are: Project 1: to assess the effect of genetic determinants of host response on malarial anemia in three prospective clinical investigations: (i) a population-based study in Suan Phung village, Ratchaburi Province, (ii) a case-control study in Bongti, Kanchanburi, and (iii) a hospital-based study in Bangkok; Project 2: to determine if excessive activity of the T helper lymphocyte type 1 (Th-1) immune response and decreased activity of the Th-2 immune response are involved in the pathogenesis of severe anemia and children and adults with Plasmodium falciparum malaria; and Project 3: to determine the role of host genetic factors in artemisinin action. The three component projects will share common resources provided by two scientific core facilities: the Genetic Core Unit and the Central Laboratory and Data Coordinating Core Unit. The overall goal of the proposed research is to provide fundamental new insights about genetic and immunological determinants of both host resistance to malaria and host response to anti-malarial therapy.